Blinatumomab in Treating Younger Patients With Relapsed B-cell Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To compare disease free survival (DFS) of high-risk (HR) and intermediate-risk (IR)
relapse B-cell acute lymphoblastic leukemia (B-ALL) patients who are randomized following
induction block 1 chemotherapy to receive either two intensive chemotherapy blocks or two
5-week blocks of blinatumomab (HR/IR randomization).

II. To compare the DFS of low risk (LR) relapse B-ALL patients who are randomized following
block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab
(LR randomization).

SECONDARY OBJECTIVES:

I. To compare overall survival (OS) of HR and IR relapse B-ALL patients who are randomized
following induction block 1 chemotherapy to receive either two intensive chemotherapy blocks
or two 5-week blocks of blinatumomab (HR/IR randomization).

II. To compare OS of LR relapse B-ALL patients who are randomized following block 1
chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR
randomization).

EXPLORATORY OBJECTIVES:

I. To compare the rates of minimal residual disease (MRD) >= 0.01% at the end of block 2 and
block 3 for HR and IR relapse B-ALL patients in HR/IR randomization.

II. To estimate, for treatment failure (TF) patients not previously receiving blinatumomab,
the hematologic complete remission rate (CR), rate of MRD < 0.01%, and proportion able to
proceed to hematopoietic stem cell transplant (HSCT) in CR after treatment with blinatumomab.

III. To assess the feasibility and safety of rapid taper of immune suppression for the subset
of HSCT patients with MRD >= 0.01% pre- and/or post-HSCT with no acute graft versus host
disease (aGVHD).

IV. To evaluate blinatumomab pharmacokinetics (PK) and explore exposure-response
relationships for measures of safety and effectiveness.

OUTLINE:

All patients receive Block 1 over 4 weeks.

BLOCK 1: Patients receive dexamethasone orally (PO) twice daily (BID) or intravenously (IV)
on days 1-5 and 15-19; vincristine sulfate IV over 1 minute on days 1, 8, 15, and 22;
pegaspargase IV over 1-2 hours on days 3 and 17; and mitoxantrone hydrochloride IV over 15-30
minutes on days 1-2. Patients with central nervous system (CNS) 1 or CNS2 also receive
methotrexate intrathecally (IT) on days 1 and 8. Patients with CNS3 or isolated CNS relapse
also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1, 8, 15, and 22.
High risk and intermediate risk patients are then assigned to randomization R1. Low risk
patients are assigned to randomization R2.

RANDOMIZATION R1 (HR and IR patients): Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo
allogeneic HSCT.

ARM B: Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks,
and then undergo allogeneic HSCT.

RANDOMIZATION R2 (LR patients): Patients are then randomized to 1 of 2 treatment arms.

ARM C: Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8
weeks, Continuation 2 over 8 weeks, and then Maintenance.

ARM D: Patients receive Block 2 over 4 weeks, Blinatumomab Block 2 over 5 weeks, Continuation
1 over 8 weeks, Blinatumomab Block 3 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab
Block 3 over 5 weeks, and then Maintenance.

BLOCK 2: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine sulfate IV over
1 minute on day 1; methotrexate IV over 36 hours on day 8; leucovorin calcium IV or PO on
days 10-11; pegaspargase IV over 1-2 hours on day 9 or 10; cyclophosphamide IV over 15-30
minutes on days 15-19; and etoposide IV over 1-2 hours on days 15-19. Patients with CNS1 or
CNS2 also receive methotrexate IT on day 8. Patients with CNS3 also receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on days 8 and 22.

BLOCK 3: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine sulfate IV over
1 minute on day 1; cytarabine IV over 3 hours every 12 hours on days 1, 2, 8, and 9;
asparaginase intramuscularly (IM) or IV over 1 hour on days 2, 4, 9, 11, and 23; methotrexate
IT on day 1 and IV over 36 hours on day 22; leucovorin calcium PO or IV on days 24-25.
Patients with CNS1 or CNS2 also receive methotrexate IT on day 22. Patients with CNS3 also
receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 22.

BLINATUMOMAB BLOCK 1: Patients dexamethasone PO or IV on day 1 and blinatumomab IV
continuously on days 1-28. Patients with CNS1 or CNS2 also receive methotrexate IT on days 15
and 29. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT
on days 15 and 29.

BLINATUMOMAB BLOCK 2: Patients blinatumomab IV continuously on days 1-28. Patients with CNS1
or CNS2 also receive methotrexate IT on days 8 and 29. Patients with CNS3 also receive
methotrexate IT, hydrocortisone IT, and cytarabine IT on days 8 and 29.

BLINATUMOMAB BLOCK 3: Patients blinatumomab IV continuously on days 1-28 and dexamethasone PO
or IV on day 1.

CONTINUATION 1 & 2: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine
sulfate IV over 1 minute on day 1; mercaptopurine tablet PO on days 1-42; methotrexate PO on
days 8, 15, 29, and 36; leucovorin calcium PO or IV on day 24-25 (patients with CNS1, CNS2,
or CNS3); cyclophosphamide IV over 15-30 minutes on days 43 and 50; etoposide IV over 1-2
hours on days 43 and 50; thioguanine PO once daily on days 43-49; and cytarabine IV over 1-30
minutes or subcutaneously (SC) on days 44-47 and 51-54. Patients with CNS1 or CNS2 also
receive methotrexate IT on days 1 and 43. Patients with CNS3 also receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on days 1 and 43; methotrexate PO every 6 hours on day
22; and methotrexate IV over 36 hours on day 22.

MAINTENANCE: Patients receive dexamethasone PO BID or IV on days 1-5, 29-33, and 57-61;
vincristine sulfate IV over 1 minute on days 1, 29, and 57; mercaptopurine tablet PO on days
1-84; and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Patients
with CNS1 or CNS2 also receive methotrexate IT on day 1. Patients with CNS3 also receive
methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1. Cycles repeat every 12 weeks
for up to 2 years since the beginning of treatment in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up annually for 10 years.

Inclusion Criteria:

- First relapse of B-ALL, allowable sites of disease include isolated bone marrow,
combined bone marrow and CNS and/or testicular, and isolated CNS and/or testicular;
extramedullary sites are limited to the CNS and testicles

- No waiting period for patients who relapse while receiving standard maintenance
therapy

- Patients who relapse on frontline therapy in phases other than maintenance must have
fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy,
or radiotherapy prior to entering this study

- Cytotoxic therapy: at least 14 days since the completion of cytotoxic therapy with the
exception of hydroxyurea, which is permitted up to 24 hours prior to the start of
protocol therapy, or maintenance chemotherapy, or intrathecal chemotherapy
(methotrexate strongly preferred) administered at the time of the required diagnostic
lumbar puncture to establish baseline CNS status

- Biologic (anti-neoplastic) agent: at least 7 days since the completion of therapy with
a biologic agent; for agents that have known adverse events occurring beyond 7 days
after administration, this period must be extended beyond the time during which
adverse events are known to occur

- Stem cell transplant or rescue: patient has not had a prior stem cell transplant or
rescue

- Patient has not had prior treatment with blinatumomab

- With the exception of intrathecal chemotherapy (methotrexate strongly preferred;
cytarabine is permissible) administered at the time of the required diagnostic lumbar
puncture to establish baseline CNS status, patient has not received prior
relapse-directed therapy (i.e., this protocol is intended as the INITIAL treatment of
first relapse)

- Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

- 1 to < 2 years: =< 0.6 mg/dL

- 2 to < 6 years: =< 0.8 mg/dL

- 6 to < 10 years: =< 1 mg/dL

- 10 to < 13 years: =< 1.2 mg/dL

- 13 to < 16 years: =< 1.5 mg/dL (males) and =< 1.4 mg/dL (females)

- >= 16 years: =< 1.7 mg/dL (males) and =< 1.4 mg/dL (females)

- Direct bilirubin < 3.0 mg/dL

- Shortening fraction of >= 27% by echocardiogram, or

- Ejection fraction of >= 50% by radionuclide angiogram

- All patients and/or their parent or legal guardian must sign a written informed
consent

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met

Exclusion Criteria:

- Patients with Philadelphia chromosome positive/breakpoint cluster region protein
(BCR)-Abelson murine leukemia viral oncogene homolog 1 (ABL1)+ ALL are not eligible

- Patients with Burkitt leukemia/lymphoma or mature B-cell leukemia are not eligible

- Patients with T-lymphoblastic leukemia (T-ALL)/lymphoblastic lymphoma (T-LL) are not
eligible

- Patients with B-lymphoblastic lymphoma (B-LL) are not eligible

- Patients with known optic nerve and/or retinal involvement are not eligible; patients
who are presenting with visual disturbances should have an ophthalmologic exam and, if
indicated, a magnetic resonance imaging (MRI) to determine optic nerve or retinal
involvement

- Patients known to have one of the following concomitant genetic syndromes: Down
syndrome, Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome,
Shwachman syndrome or any other known bone marrow failure syndrome

- Patients with known human immunodeficiency virus (HIV) infection

- Patients with known allergy to mitoxantrone, cytarabine, or both etoposide and
etoposide phosphate (Etopophos)

- Lactating females who plan to breastfeed

- Patients who are pregnant since fetal toxicities and teratogenic effects have been
noted for several of the study drugs; a pregnancy test is required for female patients
of childbearing potential

- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation

- Patients with pre-existing significant central nervous system pathology that would
preclude treatment with blinatumomab, including: history of severe brain injury,
dementia, cerebellar disease, organic brain syndrome, psychosis, coordination/movement
disorder, or autoimmune disease with CNS involvement are not eligible; patients with a
history of cerebrovascular ischemia/hemorrhage with residual deficits are not
eligible; (patients with a history of cerebrovascular ischemia/hemorrhage remain
eligible provided all neurologic deficits have resolved)

- Patients with uncontrolled seizure disorder are not eligible; (patients with seizure
disorders that do not require antiepileptic drugs, or are well controlled with stable
doses of antiepileptic drugs remain eligible)